Main interests

Alzheimer’s disease (AD) is the most frequent synaptic disorder of the increasingly aging population. It is uncertain if the current therapeutic strategies based on late disease events and on research on familial forms of AD (fAD) will benefit the 99% of AD patients with unknown etiology. The late onset AD etiology is likely multifactorial, with aging being the biggest risk factor and genetic predisposition likely accelerating the disease onset.
The lack of successful therapies is in part due to the irreversible neurodegeneration already installed in the affected patients. We have shown that early synaptic dysfunction is a major reversible target (Almeida et. Al, 2005; Snyder et-al 20015).
Now our focus is to determine the causal mechanisms of synaptic dysfunction in the common Late-onset Alzheimer’s disease (LOAD). Aging is the main risk factor for AD, but the contribution of intrinsic neuronal aging to LOAD is unkown. Several endocytic regulators were identified as LOAD genetic risk factors indicating endolysosomal dysfunction as a major cellular AD mechanism however how it contributes to LOAD is unclear.
Thus, we hypothesize that neuronal endolysosomal dysfunction, either by aging or genetic risk factors, contributes to synaptic dysfunction in LOAD.

Research Areas

Our aims are:
1. Does deregulation of endosomal sorting drive synaptic dysfunction?
BIN1 and CD2AP, two top ten GWAS genes are regulators of endosomal trafficking and actin dynamics(20, 28). We found that Bin1 and CD2AP loss of function increase endogenous Aβ production(21). We showed that both enhance APP access to β- and γ-secretases at sorting endosomes by distinct mechanisms of endosomal sorting(21).
We are investigating the impact of AD variants in Bin1 and CD2AP on intraneuronal Aβ42 by semi-quantitative single cell immunofluorescence, on APP and its secretases trafficking by pulse-chase assays, morphological and molecular analysis using imaging and biochemistry assays using mouse primary neurons, or alternatively in Neuro2a cell line we are developing in collaboration with C. Brito (iBET) induced human neurons edited with AD variants using Crispr/CAS9 in collaboration with A. Gontijo (CEDOC).

2. Does neuronal endocytic trafficking become dysfunctional with neuronal aging and have an impact on synapses?
Multiple mechanisms intrinsic to aging neurons likely drive synaptic decline. We are investigating investigate how age-related endocytic trafficking dysfunction drives aging-synaptic decline using in mouse primary neurons aged in vitro.
Overall, we aim to identify novel cellular and molecular mechanisms that deregulate the endolysosomal pathway in normal aging and upon LOAD genetic risk, establishing causality between aging and genetic variants and the development of LOAD.
Ultimately, we hope to determine the mechanisms underlying synaptic decline in aging neurons to identify novel therapeutic targets to delay or prevent AD.